Hypoglycemic hydroxyurea derivatives

ABSTRACT

Certain 1-(benzyl or 5-benzofuranylmethyl)-1-hydroxyurea derivatives are useful as hypoglycemic and hypocholesterolemic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 08/279,322filed Jul. 22, 1994, now abandoned, which is a divisional of applicationSer. No. 07/983,538 filed Feb. 22, 1993, now U.S. Pat. No. 5,334,604,which is a National Filing based on PCT/US91/04352 filed internationallyon Jun. 26, 1991 as a continuation of U.S. application Ser. No.07/572,745 filed Aug. 23, 1990, abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to certain compounds of the formulas (I)and (II), depicted below, having utility as hypoglycemic andhypocholesterolemic agents, methods for their use and pharmaceuticalcompositions containing them, and intermediates useful in theirsynthesis.

In spite of the early discovery of insulin and its subsequentwide-spread use in the treatment of diabetes, and the later discoveryand use of sulfonylureas (e.g. chlorpropamide, tolbutamide,acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oralhypoglycemic agents, the treatment of diabetes remains less thansatisfactory. The use of insulin, necessary in about 10% of diabeticpatients in which synthetic hypoglycemic agents are not effective (TypeI diabetes, insulin dependent diabetes mellitus), requires multipledaily doses, usually by self injection. Determination of the properdosage of insulin requires frequent estimations of the sugar in theurine or in the blood. The administration of an excess dose of insulincauses hypoglycemia, with effects ranging from mild abnormalities inblood glucose or coma, or even death. Treatment of non-insulin dependentdiabetes mellitus (Type II diabetes) usually consists of a combinationof diet, exercise, oral agents, e.g., sulfonylureas, and in more severecases, insulin. However, the clinically available hypoglycemics areunfortunately fraught with other toxic manifestations which limit theiruse. In any event, where one of these agents may fail in an individualcase, another may succeed. A continuing need for hypoglycemic agents,which may be less toxic or succeed where others fail, is clearlyevident.

Furthermore, atherosclerosis, a disease of the arteries, is recognizedto be the leading cause of death in the United States and WesternEurope. The pathological sequence leading to atherosclerosis andocclusive heart disease has been described in detail by Ross and Glomsetin New England Journal of Medicine 295 369-377 (1976) The earliest stagein this sequence is the formation of "fatty streaks" in the carotid,coronary and cerebral arteries and in the aorta. These lesions areyellow in color due to the presence of lipid deposits found principallywithin smooth-muscle cells and in macrophages of the intima layer of thearteries and aorta. Cholesterol and cholesteryl ester account for mostof this lipid. Further, it is postulated that most of the cholesterolfound within the fatty streaks results from uptake from the plasma.These fatty streaks, in turn, give rise to development of the "fibrousplaque" which consists of accumulated intimal smooth muscle cells ladenwith lipid and surrounded by extra cellular lipid, collagen, elastin andproteoglycans. The cells plus matrix form a fibrous cap that covers adeeper deposit of cell debris and more extracellular lipid. The lipid isprimarily free and esterified cholesterol. The fibrous plaque formsslowly, and is likely in time to become calcified and necrotic,advancing to the "complicated lesion" which accounts for the arterialocclusion and tendency toward mural thrombosis and arterial muscularspasm that characterize advanced atherosclerosis.

Epidemiological evidence has firmly established hyperlipidemia as aprimary risk factor in causing cardiovascular disease (CVD) due toatherosclerosis. In recent years, leaders of the medical profession haveplaced renewed emphasis on lowering plasma cholesterol levels, and lowdensity lipoprotein cholesterol in particular, as an essential step inprevention of CVD. The upper limits of "normal" are now known to besignificantly lower than heretofore appreciated. As a result, largesegments of Western populations are now realized to be at high risk fordevelopment or progression of CVD because of this factor. Individualswho possess independent risk factors in addition to hyperlipidemia areat particularly high risk. Such independent risk factors include glucoseintolerance, left ventricular hypertrophy hypertension, and being of themale sex. Cardiovascular disease is especially prevalent among diabeticsubjects, at least in part because of the existence of multipleindependent risk factors. Successful treatment of hyperlipidemia in thegeneral population, and in diabetic subjects in particular, is thereforeof exceptional medical importance.

The first step in recommended therapeutic regimens for hyperlipidemia isdietary intervention. While diet alone produces adequate response insome individuals, many others remain at high risk and must be treatedfurther by pharmacological means. New drugs for the treatment ofhyperlipidemia are, therefore, of great potential benefit for largenumbers of individuals at high risk of developing CVD. Further,successful treatment of both the hyperlipidemia and hyperglycemiaassociated with the diabetic state with a single therapeutic agent isparticularly desirable.

In addition to the hypoglycemic agents cited above, a variety of othercompounds have been reported to possess this type of activity, asreviewed by Blank [Burger's Medicinal Chemistry, Fourth Edition, PartII, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].

Schnur, in U.S. Pat. Nos. 4,342,771, 4,367,234 and 4,617,312, disclosesvarious hypoglycemic oxazolidine-2,4-diones and thiazolidine-2,4-dionessubstituted at the 5-position with aryl or heteroaryl groups.

Kawamatsu et al., U.S. Pat. No. 4,340,605, disclose hypoglycemicthiazolidine-2,4-dione compounds of the formula ##STR1## wherein R^(e)is a bond or lower alkylene and when R^(d) is an optionally substitutedfive- or six-membered heterocyclic group including one or twohetero-atoms selected from N, O and S, L¹ and L² may each be defined ashydrogen. See also Sohda et al., Chem. Pharm. Bull. Japan, Vol. 30, pp.3580-3600 (1982). PG,6

Eggler et al., U.S. Pat. No. 4,703,052, disclose hypoglycemicthiazolidinediones of the formula ##STR2## where the dotted linerepresents an optional bond, R^(f) is H, methyl or ethyl, X^(b) is O, S,SO, SO₂, CH₂, CO, CHOH or NR^(k), R^(k) is H or an acyl group and thenumerous definitions of R^(g), R^(h), R^(i) and R^(j) include R^(g),R^(h) and R^(i) as hydrogen or methyl and R^(j) as optionallysubstituted phenyl, benzyl, phenethyl or styryl. EP 283,035A and EP299,620A describe structurally related benzoxazole and benzofuranderivatives as antidiabetic agents.

Clark et al., in published World patent applications W089/08650,WO89/8651 and WO89/08652 disclose hypoglycemic thiazolidinediones whichcollectively include compounds of the type: ##STR3## wherein --------represents a bond or no bond; W is O, CO, CH₂, CHOH, or --CH═CH--; s is0, 1 or 2; X^(a) is S, O, NR^(a), --CH═CH--, --CH═N-- or --N═CH--; andY^(a) is CH or N.

SUMMARY OF THE INVENTION

The present invention is directed to compounds having the formulas##STR4## wherein

R is hydrogen or (C₁ -C₃)alkyl

R¹ and R² are taken together and are carbonyl; or R¹ and R² are takenseparately, R¹ is hydrogen or R⁴, and R² is COR⁵ or COOR⁵ ;

R³, R⁴ and R⁵ are each independently (C₁ -C₉)alkyl (C₃ -C₇) cycloalkyl,phenyl, naphthyl, furyl, benzofuryl or thienyl or one of said groupsmono- or disubstituted with (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy, (C₁-C₃)alkoxycarbonyl, trifluoromethyl, fluoro or chloro; and

n is 0 or 1; and

the pharmaceutically-acceptable cationic salts thereof.

In the present compounds, the preferred value of R is methyl; thepreferred values of R¹ are hydrogen, (C₁ -C₄) alkyl or phenyl; thepreferred value of R² is COOR⁵ where R⁵ is (C₁ -C₄)alkyl or phenyl; thepreferred values of R³ are (C₄ -C₈ ) alkyl, (C₃ -C₆) cycloalkyl, phenyl(optionally substituted by methyl, methoxy or trifluoromethyl),naphthyl, furyl and benzofuranyl.

The present compounds are generally acidic, such that the expression"pharmaceutically-acceptable cationic salts" is intended to define butnot limited to such salts as an alkali metal salt (e.g., Na, K), analkaline earth salt (e.g., Ca, Mg) or an amine salt (e.g.,dicyclohexylamine, diethanolamine, meglumine). Conventional methods areused to prepare such salts.

Also embraced by the present invention are pharmaceutical compositionsfor use in treating a hyperglycemic mammal or a hypercholesterolemicmammal which comprise a blood glucose lowering amount or a bloodcholesterol lowering amount of a compound of formula (I) or (II) and apharmaceutically-acceptable carrier. The invention further comprises amethod of lowering blood glucose in a hyperglycemic mammal whichcomprises administering to said mammal a blood glucose loweringeffective amount of a compound of formula (I) or (II); and a method oflowering blood cholesterol in a hypercholesterolemic mammal whichcomprises administering to said mammal a blood cholesterol loweringamount of a compound of the formula (I) or (II). The preferred use ofthe present compounds relates to the treatment of hyperglycemic mammals,especially man.

The present invention is also directed to intermediate compounds of theformulas ##STR5## wherein n, R and R³ are as defined above, R⁶ ishydrogen or independently a value of R³ as defined above, and R⁷ ishydrogen or a conventional hydroxy protecting group. Useful hydroxyprotecting groups include those removable by selective hydrogenation(e.g., benzyl, benzyloxycarbonyl).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The compounds of the formulas (I) and (II) of the present invention arereadily prepared. Those compounds wherein R¹ and R² are taken togetherand are carbonyl, forming a 1,2,4-oxazolidine-3,5-dione ring, are bestprepared from the corresponding precursor of the formula (III) or (IV),wherein each of R⁶ and R⁷ are hydrogen, by the action of substantiallyone molar equivalent of a chloroformate ester (preferably a (C₁-C₄)alkyl chloroformate such as ethyl chloroformate) in the presence ofexcess molar equivalents of a strong base (e.g. 2-3 molar equivalents of2N NaOH) in a reaction-inert organic solvent (preferably a relativelypolar ether such as tetrahydrofuran). The reaction is generally carriedout under relatively dilute conditions (e.g. about 1-2% w/v of substrateand organic solvent). Temperature is not critical and will generally bein the range of about 0°-50° C., conveniently ambient temperature so asto avoid the cost of heating or cooling the reaction mixture.

As used above and elsewhere herein, the expression "reaction inertsolvent" refers to a solvent which does not interact with startingmaterials, reagents, intermediates or products in a manner whichadversely affects the yield of the desired product.

The same or related reagents (e.g., simple acid chlorides) are used toprepare compounds of the formula (I) and (II) wherein R¹ and R² aretaken separately, generally limiting the base and the chloroformate (R⁵OCOCl) or acid chloride (R⁵ COCl) to substantially one molar equivalent.Solvent and base are not critical. With an aqueous solvent, thepreferred bases are NaOH or KOH, while in an organic solvent (e.g.,tetrahydrofuran, methylenechloride) a tertiary amine such astriethylamine is generally preferred.

The required hydroxyurea precursors are conveniently prepared bydeprotection of protected hydroxyurea of the formula (III) or (IV)wherein R⁷ is a hydroxy protecting group. The preferred protectinggroup, which is benzyl, is readily removed by conventionalhydrogenolysis over a noble metal catalyst in a reaction-inert solvent.The preferred catalyst is Pd/C using moderate temperatures andpressures. Alternatively, the benzyl group is removed by the action of alarge excess of ammonium formate (e.g., 4-5 molar equivalents) under theinfluence of Pd/C catalyst in a solvent such as ethanol, generally at asomewhat elevated temperature, e.g., in the range of about 30°-70° C.

Another convenient synthesis of present intermediate hydroxyureas is bythe action of an isocyanate on the corresponding hydroxylamine: ##STR6##This reaction is generally carried out in a reaction-inert solvent, suchas methylene chloride, using substantially molar equivalent amounts ofthe reagents. The temperature of this reaction is not critical, withtemperatures in the range 0°-50° C. generally satisfactory and ambienttemperature particularly convenient.

The starting protected hydroxyureas are prepared by multistep methodsgenerally employing organic reaction steps analogous to those known inthe art. These are illustrated in Preparations detailed below.

The cationic salts of the present invention are prepared by reacting theacidic form of the present compounds with a base, e.g., NaOH, Na₂ CO₃,K₂ CO₃, Ca(OH)₂, NH₃, dicyclohexylamine, etc. At least one molarequivalent and frequently a molar excess of the base is employed. Thefree acid and the base are usually combined in a co-solvent from whichthe desired salt precipitates, or can be otherwise isolated byconcentration and/or addition of a non-solvent.

The present compounds of the formulas (I) and (II) are readily adaptedto clinical use as hypoglycemic or hypocholesterolemic agents. Theactivity required for this former clinical use is defined by the testfor hypoglycemic effect in ob/ob or db/db mice by the followingprocedure:

Five to eight week old C57BL/6J-ob/ob or C57BL/K_(s) J-db/db mice(obtained from Jackson Laboratory, Bar Harbor, Maine) were housed fiveper cage under standard animal care practices. After a one weekacclimation period, the animals were weighed and 25 microliters of bloodwas collected via an ocular bleed prior to any treatment. The bloodsample was immediately diluted 1:5 with saline containing 2.5 mg/mlsodium fluoride and 2% sodium heparin, and held on ice for metaboliteanalysis. Animals were then dosed daily for five days with drug (5-50mg/kg), a positive control (50 mg/kg) of ciglitazone; U.S. Pat. No.4,467,902; Sohda et al., Chem. Pharm. Bull., vol. 32, pp. 4460-4465,1984), or vehicle. All drugs were administered in a vehicle consistingof 0.25% w/v methyl cellulose. On day 5, the animals were weighed againand bled (via the ocular route) for blood metabolite levels. The freshlycollected samples were centrifuged for two minutes at 10,000 xg at roomtemperature. The supernatant was analyzed for glucose, for example, bythe ABA 200 Bichromatic Analyzer™, using the A-gent™ glucose UV reagentsystem* (hexokinase method) using 20, 60 and 100 mg/dl standards. Plasmaglucose was then calculated by the equation,

    Plasma glucose (mg/dl)=Sample value×5×1.67=8.35×Sample value

where 5 is the dilution factor and 1.67 is the plasma hematocritadjustment (assuming the hematocrit is 40%). ™A registered trademark ofAbbott Laboratories, Diagnostics Division, 820 Mission Street, So.Pasadena,, Calif. 91030.

*A modification of the method of Richterich and Dauwalder,Schweizerische Medizinische Wochenschrift, 101,860 (1971).

The animals dosed with vehicle maintain substantially unchangedhyperglycemic glucose levels (e.g., 250 mg/dl), while positive controlanimals have depressed glucose levels (e.g., 130 mg/dl). Test compoundsare reported in terms of % glucose normalization. For example, a glucoselevel which is the same as the positive control is reported as 100%.

Studies such as that described below demonstrate that the compounds offormula (I) effect the lowering of serum cholesterol levels in mammals.

Female mice (strain C57Br/cd J), obtained from Jackson Laboratories, BarHarbor, Maine, are used at age 8-12 weeks, following 2-4 weeksacclimation having free access to water and standard laboratory chow.Animals are divided randomly into three groups of 6-7 animals. All threegroups are placed on a diet containing 0.75% cholesterol, 31% sucrose,15.5% starch, 20% casein, 17% cellulose, 4.5% corn oil, 5% coconut oil,0.25% cholic acid, 4% salts and 2% vitamin; permitted to feed ad lib for18 days; and dosed daily at 9-11 a.m. for the final 5 days by oralgavage, the control group with 5 ml/kg of vehicle (0.1% aqueous methylcellulose) and the test groups with the compound under study at dosesranging from 0.1 to 10 mg/kg/day in vehicle. After the fourth day ofdosing, the animals are fasted overnight, starting at 5 p.m. Thefollowing morning a fifth and final dose of the compound is administeredto the test groups and, three hours later, the animals are sacrificed bydecapitation. Blood from the body trunk is collected and allowed toclot, and the serum assayed enzymatically, using an Abbott VP automatedanalyzer, for HDL cholesterol, LDL and VLDL cholesterol, and totalcholesterol. Whether judged on the basis LDL+VLDL cholesterol levels,total cholesterol levels or the ratio of LDL+VLDL/HDL, the compounds ofthis invention generally show favorable result in lowering cholesterollevels.

The present compounds of the formulas (I) and (II) are clinicallyadministered to mammals, including man, via either the oral or theparenteral route. Administration by the oral route is preferred, beingmore convenient and avoiding the possible pain and irritation ofinjection. However, in circumstances where the patient cannot swallowthe medication, or absorption following oral administration is impaired,as by disease or other abnormality, it is essential that the drug beadministered parenterally. By either route, the dosage is in the rangeof about 0.10 to about 50 mg/kg body weight of the subject per day,preferably about 0.10 to about 10 mg/kg body weight per day administeredsingly or as a divided dose. However, the optimum dosage for theindividual subject being treated will be determined by the personresponsible for treatment, generally smaller doses being administeredinitially and thereafter increments made to determine the most suitabledosage. This will vary according to the particular compound employed andwith the subject being treated.

The compounds can be used in pharmaceutical preparations containing thecompound, or pharmaceutically acceptable acid salt thereof, incombination with a pharmaceutically-acceptable carrier or diluent.Suitable pharmaceutically-acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. The activecompound will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedabove. Thus, for oral administration the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions may, if desired, contain additional components such asflavorants, sweeteners, excipients and the like. For parenteraladministration the compounds can be combined with sterile aqueous ororganic media to form injectable solutions or suspensions. For example,solutions in sesame or peanut oil, aqueous propylene glycol and the likecan be used, as well as aqueous solutions of water-solublepharmaceutically-acceptable acid addition salts of the compounds. Theinjectable solutions prepared in this manner can then be administeredintravenously, intraperitoneally, subcutaneously, or intramuscularly,with intramuscular administration being preferred in man.

The present invention is illustrated by the following Examples. However,it should be understood that the invention is not limited to thespecific details of these examples. Nomenclature used herein is based onRigaudy and Klesney, IUPAC Nomenclature of Organic Chemistry, 1979 Ed.,Pergammon Press, New York, 1979.

EXAMPLE 1N-carbamoyl-N-ethoxycarbonyloxy-4-[2-5-methyl-2-phenyl-4-oxazolyl)ethoxyl]benzylamine (II: R=methyl, R¹ =H, R² =COOR⁵, R⁵ =C₂ H₅, R³ =C₆H₅, n=O)

To a 0° C. suspension of the product of preparation I (350 mg, 0.95mmol) and 2N NaOH (0.47 mL) was added ethyl chloroformate (0.091 mL,0.95 mmol) and the reaction allowed to warm to room temperature. Afterstirring for 1 hour, the reaction was diluted with ice water (5 mL) andacidified to pH 2 with 6N HCl. The resultant solid was collected viavacuum filtration and washed with water. Chromatography on silica gelwith 2% MeOH/CHCl₃ gave the title compound (70 mg, 17%) as a whitesolid:mp 130°-133° C.

    ______________________________________                                                      C        H      N                                               ______________________________________                                        C.sub.23 H.sub.25 N.sub.3 O.sub.6                                                          calc   62.86      5.73 9.56                                                   fnd    62.44      5.54 9.26                                      ______________________________________                                    

By the same method, the following additional compounds of the formula(II) wherein R is methyl, R¹ is hydrogen and R² is COOR⁵ were preparedfrom corresponding hydroxy ureas of the formula (IV) wherein R⁶ and R⁷and are each hydrogen and chloroformate ester (R⁵ OCOCl):

    ______________________________________                                                             Yield                                                    R.sup.3 n     R.sup.5                                                                              (%)    mp (°C.)                                                                      C    H    N                                ______________________________________                                        Ph      0     Me     33     153-156                                                                              60.19                                                                              5.63 9.57.sup.a                                                                    (calc)                                                              60.32                                                                              5.32 9.12                                                                          (fnd)                            Ph      0     iBu    22     101-103                                                                              64.23                                                                              6.25 8.99                                                                64.14                                                                              6.09 8.72                             Ph      0     Ph     11     130-132                                                                              65.91                                                                              5.22 8.54.sup.b                                                          65.90                                                                              4.90 8.32                             2-furyl 0     Me     25     119-121                                                                              57.83                                                                              5.10 10.12                                                               57.46                                                                              5.08 9.92                             2-furyl 0     Et     31     foam                                              2-furyl 0     iBu    49     102-103                                                                              60.39                                                                              5.95 9.19                                                                60.09                                                                              5.73 9.02                             2-furyl 0     Ph     30     136-138                                                                              62.89                                                                              4.86 8.80                                                                62.47                                                                              4.72 9.05                             2(OMe)Ph                                                                              0     Me      7     143-145                                           2(OMe)Ph                                                                              0     Et      6      99-103                                                                              58.05                                                                              6.09 8.46.sup.c                                                          58.38                                                                              5.80 7.82                             4(CF.sub.3)Ph                                                                         0     Me     21     173-174                                                                              55.59                                                                              4.49 8.52                                                                55.64                                                                              4.32 8.22                             4(CF.sub.3)Ph                                                                         0     Et     19     165-168                                                                              56.80                                                                              4.77 8.28                                                                56.65                                                                              4.65 8.10                             4(CF.sub.3)Ph                                                                         0     iBu    13     148-150                                                                              58.32                                                                              5.27 7.85                                                                58.16                                                                              5.22 7.72                             4(CF.sub.3)Ph                                                                         0     Ph     17     173-175                                                                              59.57                                                                              4.46 7.44.sup.d                                                          59.39                                                                              3.90 7.38                             Bu      1     Me     18     81-84                                             Bu      1     Et     18     93-94  60.32                                                                              7.25 9.59.sup.b                                                          60.12                                                                              7.12 9.69                             Bu      1     iBu    49     104-106                                                                              62.45                                                                              7.64 9.10                                                                62.43                                                                              7.88 9.16                             cPr     1     Me     37     100-103                                                                              57.61                                                                              6.41 10.08.sup.a                                                         57.69                                                                              5.85 9.82                             cPr     1     Et     46     104-106                                           cPr     1     iBu    48     96-98  62.00                                                                              7.01 9.43                                                                61.68                                                                              6.74 9.43                             cPr     1     Ph     16     115-117                                                                              63.68                                                                              5.91 8.91.sup.e                                                          63.36                                                                              5.47 8.84                             2-naphthyl                                                                            0     Me      8     123-127                                           2-bzfuryl                                                                             0     Me     20     149-151                                                                              60.75                                                                              5.10 8.86.sup.d                                                          60.69                                                                              4.71 8.68                             2-bzfuryl                                                                             0     Et     45     130-132                                                                              60.90                                                                              5.42 8.52.sup.a                                                          60.57                                                                              5.01 8.25                             ______________________________________                                         .sup.a 0.75 hydrate                                                           .sup.b 0.25 hydrate                                                           .sup.c 1.5 hydrate                                                            .sup.d 0.50 hydrate                                                           .sup.e 0.33 hydrate                                                           Ph = phenyl                                                                   Me = methyl                                                                   Et = ethyl                                                                    Bu = butyl                                                                    iBu = isobutyl                                                                cPr = cyclopropyl                                                             bzfuryl = benzofuranyl                                                   

EXAMPLE 25-[(1,2,4-Oxadiazolidine-3,5-dion-2-yl)methyl]-2[(5-methyl-2-(4-methylphenyl)-4-oxazolyl)-methyl]benzofuran [I, R=CH₃, R¹ +R² =CO, R³ =4(CH₃)C₆ H₄,n=0]

To a 0° C. suspension of the product of Preparation Y (1.39 g, 3.55mmol), THF (90 mL) and 2N NaOH (5.33 mL, 10.7 mmol) was added ethylchloroformate (0.35 mL, 3.69 mmol) in a dropwise fashion. After stirringat room temperature the reaction was cooled to 0° C., diluted with water(200 mL) and adjusted to pH 2 with 6N HCl. The THF was removed with astream of nitrogen and the resultant solid was collected by vacuumfiltration. Chromatography on silica gel utilizing a gradient elution ofCHCl₃ to 2% MeOH/CHCl₃ gave the title compound (950 mg, 64%) as a yellowsolid: mp 201°-203° C.

    ______________________________________                                                      C        H      N                                               ______________________________________                                        C.sub.22 H.sub.19 N.sub.3 O.sub.5                                                          calc   66.18      4.59 10.07                                                  fnd    66.15      4.49 9.70                                      ______________________________________                                    

By the same method, the following additional compounds were preparedfrom the corresponding hydroxyureas:

5-[(1,2,4-Oxadiazolidine-3,5-dion-2-yl)methyl]-2-[(5-methyl-2-(2-furyl)-4-oxazolyl)methyl]benzofuran;74% yield; mp 191°-193° C.

5-[(1,2,4-Oxadiazolidine-3,5-dion-2-yl)methyl]-2-[(5-methyl-2-phenyl-4-oxazolyl)methyl]benzofuran;27% yield; mp 89°-91° C.

2-[[4-(2-(5-methyl-2-cyclopropylmethyl-4-oxazolyl)ethoxy)phenyl]methyl]-1,2,4-oxazolidine-3,5-dione; 52% yield; mp139°-141° C.

Substituting an equivalent amount of methyl chloroformate for ethylchloroformate, the same method was used to prepare the followingadditional compounds from the corresponding hydroxyureas:

2-[[4-(2-(5-methyl-2-(4-methoxyphenyl)-4-oxazolyl)ethoxy)phenyl]methyl]-1,2,4-oxazolidine-3,5-dione; 9% yield;mp 143°-145° C.

2-[[4-(2-(5-methyl-2-(2-furyl)-4-oxazolyl)ethoxy)phenyl]methyl]-1,2,4-oxazolidine-3,5-dione; 9% yield; mp180°-183° C.

2-[[4-(2-(5-methyl-2-(2-naphthyl)-4-oxazolyl)-ethoxy)phenyl]methyl]-1,2,4-oxazolidine-3,5-dione; 15% yield; mp145°-150° C.

Substituting an equivalent amount of methyl chloroformate for ethylchloroformate and equivalent triethylamine for NaOH, the same method wasused to prepare the following additional compound from the correspondinghydroxyurea:

2-[[4-(2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy)phenyl]methyl]-1,2,4-oxazolidine-3,5-dione; 19% yield; mp 148°-150° C.

EXAMPLE 3N-(Methoxycarbonyloxy)-N-(methylaminocarbonyl)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]benzylamine

To a suspension of the product of Preparation J (185 mg, 0.49 mmol) inCH₂ Cl₂ (4 mL) was added triethylamine (0.070 mL, 0.53 mmol). Aftercooling to 0° C., methyl chloroformate (0. 041 mL, 0.53 mmol) was addedand the reaction stirred for 1.5 hours at 10° C. It was then dilutedwith CH₂ Cl₁₂ (20 mL), washed with water (2×10 mL), dried (Na₂ SO₄),filtered and concentrated. Chromatography on silica gel eluting with 1/3ethyl acetate:hexanes gave the title compound (60 mg, 29%) as a whitesolid: mp 134°-135° C.

    ______________________________________                                                         C       H      N                                             ______________________________________                                        C.sub.23 H.sub.25 N.sub.3 O.sub.6.0.25H.sub.2 O                                               calc   62.22     5.79 9.47                                                           62.29     5.72 8.85                                    ______________________________________                                    

By the same method, the following additional compounds were preparedfrom the corresponding hydroxyureas:

N-(ethoxycarbonylmethylaminocarbonyl)-N-(methoxycarbonyloxy)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]benzylamine;58% yield; mp 107°-108° C.

N-[(1-methylethyl)aminocarbonyl]-N-(methoxycarbonyloxy)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylamine; 52% yield; mp111°-113° C.

By the same method, N-(methoxycarbonyloxy)-N-(phenylaminocarbonyl)-4-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]benzylamine is prepared fromthe corresponding phenyl-hydroxyurea of Preparation J.

PREPARATION A Methyl 3-Carboxy-3-(2-furoylamino) propionate

To a 0° C. solution of beta-methyl aspartate hydrochloride (100 g, 0.545mol), CH₂ Cl₂ (1 L) and triethylamine (167 mL, 1.2 mol) was added asolution of CH₂ Cl₂ (100 mL) and furoyl chloride (71.1 g, 0.545 mol) ina dropwise fashion over 1 hour. The reaction was then stirred for 1 hourat room temperature, quenched by the addition of water (500 mL) andadjusted to pH 2 with conc. HCl. The aqueous layer was separated andextracted with CH₂ Cl₂ (250 mL). The combined organic layers were dried(MgSO₄), filtered and evaporated to give a yellow oil (130 g, 99%).

Also prepared by this method were methyl 3-carboxy-3-(acylamino)propionate esters as follows:

    ______________________________________                                        Acyl Group       Yield (%) mp (°C.)                                    ______________________________________                                        benzoyl          41        148-150                                            2(MeO)C.sub.6 H.sub.4 CO                                                                       100       (oil)                                              4(CF.sub.3)C.sub.6 H.sub.4 CO                                                                  98        (foam)                                             n-C.sub.5 H.sub.11 CO                                                                          100       (oil)                                              (c-C.sub.3 H.sub.5)CH.sub.2 CO                                                                 11        (oil)                                              2-benzofuroyl    86        (foam)                                             2-naphthoyl      62        122-135                                            ______________________________________                                    

PREPARATION B Methyl 3-(2-Furoylamino)-4-oxopentanoate

To a solution of the product of Preparation A (126 g, 0.522 mol) inpyridine (273 mL) was added acetic anhydride (345 mL) anddimethylaminopyridine (3.5 g). The reaction was heated to 93° C. for 2.5hours, removed from the oil bath and then water (220 mL) was cautiouslyadded in small increments. The reaction was then heated for anadditional 20 minutes at 90° C., cooled to room temperature and dilutedwith water (1 L). This was then extracted with ethyl acetate (3×1 L) andthe combined organic layers washed with 10% HCl until the washings wereacidic. The organic layer was then washed with water, cautiously with 5%NaHCO₃ solution (2×500 mL) and then brine (500 mL). The solution wasdried (MgSO₄), filtered and concentrated to give a brown oil (74.2 g,59%).

Also prepared by this method were the following methyl3-(acylamino)-4-oxopentanoate esters:

    ______________________________________                                        Acyl Group       Yield (%) mp (°C.)                                    ______________________________________                                        benzoyl          43        (oil)                                              2(OMe)C.sub.6 H.sub.4 CO                                                                       93        (oil)                                              4(CF.sub.3)C.sub.6 H.sub.4 CO                                                                  70        114-119                                            n-C.sub.5 H.sub.11 CO                                                                          99        (oil)                                              (c-C.sub.3 H.sub.5)CH.sub.2 CO                                                                 53        (oil)                                              2-benzofuroyl    70        (oil)                                              2-naphthoyl      78        82-84                                              ______________________________________                                    

PREPARATION C Methyl 2-(5-Methyl-2-(2-furyl)-4-oxazolyl)acetate

To a solution of the product of Preparation B (73 g, 0.305 mol) andtoluene (360 mL) was added POCl₃ (120 mL) and the solution heated toreflux for 3 hours. The bulk of the solvent was distilled off and theresidue was added cautiously to 560 mL of ice water. The pH was adjustedto pH 7 with solid NaHCO₃ and the aqueous was extracted with ethylacetate (2×1 L). The combined organic layers were dried (MgSO₄),filtered and concentrated to give the crude product. This was purifiedby silica gel chromatography with ethyl acetate/hexanes as eluent toafford the title compound as an oil (27.2 g, 40%).

Also prepared by this method were methyl2-(5-methyl-2-substituted-4-oxazolyl)acetate esters as follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        phenyl         79        oil                                                  2(OMe)C.sub.6 H.sub.4                                                                        76        <50                                                  4(CF.sub.3)C.sub.6 H.sub.4                                                                   66        75-80                                                n-C.sub.5 H.sub.11                                                                           92        (oil)                                                (c-C.sub.3 H.sub.5)CH.sub.2                                                                  81        (oil)                                                2-benzofuryl   75        103-104                                              2-naphthyl     60        (oil)                                                ______________________________________                                    

PREPARATION D 2-(5-Methyl-2-(2-furyl)-4-oxazolyl )ethanol

To a suspension of lithium aluminum hydride (4.7 g) in dry THF (82 mL)at 0° C. was added a solution of the product of Preparation C (27.2 g,123 mmol) in THF (82 mL) over 1 hour. The solution was stirred for 1hour at room temperature, cooled to 0° C. and then quenched by thecareful sequential addition of water (5 mL), 15% NaOH (5 mL) and finallywater (15 mL). The crude reaction mixture was filtered through celite,and the residual aluminum salts washed with ether (250 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated to give thetitle compound as an oil.

Also prepared by this method were2-(5-methyl-2-substituted-4-oxazolyl)ethanol derivatives as follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        phenyl         69         48-50*                                              2(OMe)C.sub.6 H.sub.4                                                                        84        88-91                                                4(CF.sub.3)C.sub.6 H.sub.4                                                                   78        63-67                                                n-C.sub.5 H.sub.11                                                                           45        (oil)                                                (c-C.sub.3 H.sub.5)CH.sub.2                                                                  57        (oil)                                                2-benzofuryl   81        71-74                                                2-naphthyl     67        74-79                                                ______________________________________                                         *EP 0 177 353 reports 73-74° C.                                   

PREPARATION E 4-[2-(5-Methyl-2-(2-furyl)-4-oxazolyl)-ethoxy]benzonitrile

To a solution of the product of preparation D (18.4 g, 95.7 mmol),4-fluorobenzonitrile (17.4 g, 144 mmol) and THF (195 mL) at 0° C. wasadded sodium hydride (60% in oil, 4.60 g, 115 mmol) in small portions.The reaction was stirred at room temperature overnight and poured intoice water (1.5 L) and adjusted to pH 3 with acetic acid. The resultantsolids were collected by vacuum filtration and dissolved in CH₂ Cl₂. Theorganic solution was dried (MgSO₄), filtered and concentrated to givethe crude product. Recrystallization from methanol gave the titlecompound (17.6 g, 62%) as yellow needles: mp 105°-108° C.

Also prepared by this method were4-[2-(5-methyl-2-substituted-4-oxazolyl)ethoxy]benzonitrile derivativesas follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        phenyl         78         100-102*                                            2(OMe)C.sub.6 H.sub.4                                                                        99        81-83                                                4(CF.sub.3)C.sub.6 H.sub.4                                                                   100       103-108                                              n-C.sub.5 H.sub.11                                                                           51        (oil)                                                (c-C.sub.3 H.sub.5)CH.sub.2                                                                  96        (oil)                                                2-benzofuryl   100       125-127                                              2-naphthyl     82        132-135                                              ______________________________________                                         *EP 0 177 353 reports 119-120° C.                                 

PREPARATION F 4-[2-(5-Methyl-2-phenyl-4-oxazolyl)-ethoxy]benzaldehyde

A solution of the phenyl product from Preparation E (3.5 g, 11.5 mmol),75% formic acid (50 mL) and Raney Nickel (3.5 g) was heated to refluxfor 3 hours. After cooling to room temperature the reaction was filteredthrough celite and the residual solids washed with ethyl acetate (200mL). After evaporation of all of the combined filtrates, water (100 mL)was added and the resulting suspension extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with 5% NaHCO₃(2×100 mL), dried (MgSO₄), filtered and concentrated to give a yellowsolid. The title compound was isolated in two fractions (3.46 g, 98%)following trituration with hexanes: mp 70°-73° C. (lit. 82°-84° C.; EP 0177 353).

Also prepared by this method were4-[2-(5-methyl-2-substituted-4-oxazolyl)ethoxy]benzaldehyde derivativesas follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        2-furyl        quant     63-67                                                2(OMe)C.sub.6 H.sub.4                                                                        99        (crude solid)                                        4(CF.sub.3)C.sub.6 H.sub.4                                                                   97        55-80                                                n-C.sub.5 H.sub.11                                                                           100       (oil)                                                (c-C.sub.3 H.sub.5)CH.sub.2                                                                  100       (oil)                                                2-benzofuryl   58        109-116                                              2-naphthyl     88         95-101                                              ______________________________________                                    

PREPARATION G 4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxybenzaldoxime

To a solution of the product from Preparation F (4.00 g, 13.0 mmol)hydroxylamine hydrochloride (1.36 g, 19.6 mmol) in ethanol (50 mL) wasadded pyridine (2.6 mL). The reaction was heated to reflux for 1.5hours, cooled to room temperature and poured into a mixture of ethylacetate (400 mL) and water (100 mL). The organic layer was washed withwater (100 mL), brine (100 mL), dried (Na₂ SO₄), filtered andconcentrated to give the product (4.00 g, 96%) as a tan solid: mp149°-151° C.

Also prepared by this method were4-[2-(5-methyl-substituted-4-oxazolyl)ethoxy]benzaldoximes as follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        2-furyl        92        171-173                                              2(OMe)C.sub.6 H.sub.4                                                                        80        146-149                                              4(CF.sub.3)C.sub.6 H.sub.4                                                                   94        123-128                                              n-C.sub.5 H.sub.11                                                                           99        93-97                                                (c-C.sub.3 H.sub.5)CH.sub.2                                                                  94        133-135                                              ______________________________________                                    

PREPARATION HN-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]-benzyl]hydroxylamine

To a suspension of the product of Preparation G (4.03 g, 12.5 mmol) inhot methanol (280 mL) was added sodium cyanoborohydride (3.93 g, 62.5mmol) and a few crystals of methyl orange. A solution of methanol/conc.HCl (1:1) was added in a dropwise fashion until the reaction mixtureremained red-orange and heating was continued at 50° C. for 1.5 hours.The reaction was cooled to 0° C., adjusted to pH 9 with 6N NaOH andevaporated to give a yellow residue. This was then dissolved in ethylacetate (800 mL) and washed with water (200 mL) and brine (2×200 mL).The organic solution was dried (Na₂ SO₄), filtered and concentrated togive the product (3.90 g, 97%) as a solid: mp 99°-102° C.

Also prepared by this method wereN-[4-[2-(5-methyl-2-substituted-4-oxazolyl)ethoxy]benzyl]hydroxylaminederivatives as follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        2-furyl        84        113-118                                              2(OMe)C.sub.6 H.sub.4                                                                        100       (oil)                                                4(CF.sub.3)C.sub.6 H.sub.4                                                                   94        91-96                                                n-C.sub.5 H.sub.11                                                                           91        (oil)                                                (c-C.sub.3 H.sub.5)CH.sub.2                                                                  100       (oil)                                                ______________________________________                                    

PREPARATION I1-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)-ethoxy]beznyl]-1-hydroxyurea

To a suspension of the product of Preparation H (1.08 g, 3.0 mmol) and amixture of acetic acid (1.5 mL) and water (3 mL) at 35° C. was added asolution of potassium cyanate (0.52 g, 6 mmol) in water (3 mL), also at35° C. After stirring for 10 minutes at 35° C. and then 1 hour at roomtemperature, an additional portion of potassium cyanate (0.52 g, 6 mmol)in water (3 mL) was added. After stirring for 2 hours at roomtemperature, the reaction was cooled to 0° C. and the solids werecollected by vacuum filtration. This was then dissolved in CHCl₃, thewater separated and the organic layer dried (Na₂ SO₄), filtered andconcentrated to give the crude product. Chromatography on silica geleluting with MeOH/CHCl₃ gave the title compound (703 mg, 67%) as a whitesolid: mp 148°-150° C.

Also prepared by this method were1-[4-[2-(5-methyl-2-substituted-4-oxazolyl) ethoxy]benzyl]-1-hydroxyureaderivatives as follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        2-furyl        52        155-157                                              2(OMe)C.sub.6 H.sub.4                                                                        40        116-120                                              4(CF.sub.3)C.sub.6 H.sub.4                                                                   40        115-120                                              n-C.sub.5 H.sub.11                                                                           42         98-101                                              (c-C.sub.3 H.sub.5)CH.sub.2                                                                  42        (foam)                                               ______________________________________                                    

PREPARATION J 1-Hydroxy-1-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3-methylurea

To a solution of the product of Preparation H (324 mg, 1.00 mmol) andCH₂ Cl₂ (2 mL) was added methyl isocyanate (0,059 mL, 1.0 mmol). After30 minutes the solvent was removed and the resultant solid wastriturated with ether (2×5 mL) to give the title compound (267 mg, 70%)as a white solid: mp 139°-144° C.

    ______________________________________                                                         C       H      N                                             ______________________________________                                        C.sub.21 H.sub.23 N.sub.3 O.sub.4.0.75H.sub.2 O                                               calc   63.86     6.25 10.64                                                   fnd    63.83     5.76 10.47                                   ______________________________________                                    

By substituting methyl isocyanate with a molar equivalent of theappropriate isocyanate, this method was used to prepare additional1-hydroxy-1-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3-substituted-urea derivatives as follows:

    ______________________________________                                        Substituent    Yield (%) mp (°C.)                                      ______________________________________                                        (CH.sub.3).sub.2 CH                                                                          53        89-93                                                phenyl         53        166-168                                              EtO.sub.2 CCH.sub.2                                                                          69        139-141                                              ______________________________________                                    

PREPARATION K Diethyl 2-((4-Methylbenzoyl)amino) propandioate

To a suspension of diethyl aminomalonate hydrochloride (20.95 g, 97.02mmol) and dry CH₂ Cl₂ (180 mL) was added triethylamine (29.7 mL, 213mmol). After cooling to 0° C., a solution of p-toluoyl chloride (15 g,97 mmol) and CH₂ Cl₂ (25 mL) was added at a rate such that the reactiontemperature remained less than 5° C. The reaction was stirred at roomtemperature for 1 hour, cooled to 0° C. and quenched with water (90 mL).The organic layer was separated and washed with water (2×100 mL), 10%HCl (2×100 mL), water (2×100 mL) and brine (100 mL). The resultantsolution was dried (Na₂ SO₄), filtered and concentrated to give thetitle compound (26.8 g, 94%) as a white solid: mp 98°-99° C.

Also prepared by this method was diethyl 2-((2furoyl) amino)propandioate; 99% yield; mp 55°-59° C.

PREPARATION L Ethyl2-((4-Methylbenxoyl)amino-2-ethoxycarbonyl-4-pentynoate

Sodium hydride (3.7 g, 60% in oil, 92.5 mmol) was placed in a reactionvessel and washed with hexanes (4×10 mL) and then diluted with THF (400mL). A solution of the product of Preparation K (25 g, 85.2 mmol) andTHF (240 mL) was added at such a rate that the reaction temperature was<25° C. After the addition was complete the reaction was stirred at roomtemperature for 5 minutes and propargyl bromide (10.0 mL, 80% intoluene, 90.5 mmol) was added in one portion and the reaction stirredfor 5 days. The reaction was concentrated to about 100 mL and thenquenched into saturated ammonium chloride (500 mL). This was extractedwith ethyl acetate (2×500 mL) and the combined organic layers werewashed with water (200 mL) and brine (200 mL). The solution was dried(Na₂ SO₄) and concentrated to give an oil (20.7 g, 73%). Trituration ofthe oil with hexanes gave white solids: mp 70°-73° C.

Also prepared by this method was ethyl 2-((2furoyl)amino)-2-ethoxycarbonyl-4-pentynoate; 88% yield; mp 90°-93° C.

PREPARATION M 2-((4-Methylbenzoyl)amino)-4-pentynoic Acid

To a solution of the product of Preparation L (20.1 g, 60.7 mmol) andmethanol (715 mL) was added a 10% KOH in water solution over 30 minutes.After stirring overnight, the methanol was removed under reducedpressure and the resultant amber solution cooled to 0° C. and dilutedwith water (750 mL). The pH was adjusted to pH 1 with 6N HCl andextracted with ethyl acetate (2×800 mL). The combined organic layerswere washed with brine (200 mL), dried (Na₂ SO₄) filtered andconcentrated to give an amber oil.

This was suspended in xylenes (400 mL) and heated to 138° C. for 1 hour(gas evolution seen). The reaction was cooled in ice and theprecipitated tan material was collected by vacuum filtration (13.6 g,97%) to give the title compound: mp 140°-141° C.

Also prepared by this method was 2-((2-furoyl)-amino-4-pentynoic acid;88% yield; mp 106°-110° C.

PREPARATION N 3-((4-Methylbenzoyl)amino)-5-hexyn-2-one

To a solution of the product of Preparation M (13.6 g, 58.8 mmol) and4-dimethylamino pyridine (355 mg) in pyridine (31 mL) was added aceticanhydride (39 mL) and the dark reaction was heated at 93° C. for 1 hour.After cooling to room temperature, water (26 mL) was cautiously addedthrough the top of the condenser and the reaction reheated to 90° C. for20 minutes. The reaction was cooled to room temperature, diluted withwater (500 mL) and extracted with ethyl acetate (2×400 mL). The combinedorganic layers were washed with water (200 mL), 10% HCl (3×100 mL) and5% NaHCO₃ (3×100 mL). The resulting solution was dried (Na₂ SO₄),filtered and concentrated to give a brown oil which was triturated withhexanes to give the title compound (13.2 g, 98%) as a brown solid: mp84°-87° C.

Also prepared by this method was 3-((2-furoyl)-amino)-5-hexyn-2-one; 79%yield; mp 65°-67° C.

PREPARATION O 2-(4-Methylphenyl)-4-(2-propynyl)-5-methyloxazole

To a solution of the product of Preparation N (1.00 g, 4.36 mmol) intoluene (5 mL) was added POCl₃ (1.7 mL) and the reaction heated toreflux for 3 hours. The solvent was removed by distillation, and theresidue was added to ice water (20 mL). The solution was adjusted to pH7 with sodium carbonate and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with brine (20 mL), dried (Na₂ SO₄),filtered and concentrated. This was then chromatographed on silica gelwith 10/1 hexanes:ether as eluent to afford the title compound (627 mg,65%) as a yellow solid: mp 65°-68° C.

Also prepared by this method was2-(2-furyl)-4-(2-propynyl)-5-methyloxazole; 64% yield; oil.

PREPARATION P5-Formyl-2-[(5-methyl-2-(4-methylphenyl)-4-oxazolyl)methyl]benzofuran

A suspension of Cu₂ O (3.22 g, 22.5 mmol), the product of Preparation O(7.82 g, 37.0 mmol), 3-iodo-4-hydroxybenzaldehyde (7.65 g, 30.8 mmol)and bis(triphenylphosphine)palladium dichloride (169 mg, 0.24 mmol) inpyridine (100 mL) was heated to reflux for 20 hours. After cooling toroom temperature, the reaction was filtered through celite andconcentrated to a dark mass. This was then chromatographed on florisilwith 9/1 hexanes:ethylacetate as the eluent to give the title compound(6.47 g, 63%) as a yellow solid: mp 126°-130° C.

Also prepared by this method was5-formyl-2-[(5-methyl-2-(2-furyl)-4-oxazolyl)methyl]benzofuran; 89%yield; mp 125°-126° C.

PREPARATION Q 2-(2-Phenyl-5-methyloxazol-4-ylcarbonyl)-5-bromobenzofuran

To a slurry of 294 g of 5-bromosalicylaldehyde in 3 liters of dryethanol was added 79.06 g of sodium methoxide and the mixture allowed tostir for 20 minutes. To the resulting yellow slurry was added 410 g of2-phenyl-4-bromoacetyl-5-methyloxazole and the slurry heated to 78° C.for 2 hours. An additional 250 mg of sodium methoxide was added andheating continued overnight under a nitrogen atmosphere. The reactionwas cooled and the solids filtered and washed with ethanol, 393 g, mp212°-213° C.

Also prepared by this method were2-(2-substituted-5-methyloxazol-4-ylcarbonyl)-5-bromobenzofuranderivatives as follows:

    ______________________________________                                        Substituent    mp(°C.)                                                 ______________________________________                                        2-naphthyl     231-234                                                        4(CH.sub.3)C.sub.6 H.sub.4                                                                   --                                                             3(CH.sub.3)C.sub.6 H.sub.4                                                                   173-178                                                        nC.sub.6 H.sub.11                                                                            --                                                             ______________________________________                                    

PREPARATION R2-[1-(2-Phenyl-5-methyloxazol-4-yl)-1-hydroxymethyl]-5-bromobenzofuran

To a slurry of 265.44 g of the product of Preparation Q in 2.1 liters oftetrahydrofuran was added 2.5 liters of absolute methanol and the slurrycooled in an ice bath. Sodium borohydride (26.3 g) was added in fourportions over a period of 15 minutes. After stirring in the cold for 30minutes, the reaction mixture was allowed to warm to room temperature.After hour the solvent was removed in vacuo and the residue, treatedwith 3 liters of water. The solids were filtered, washed with water anddried in vacuo, 21.48 g, mp 152°-154° C.

Also prepared by this method were2-[1-(2substituted-5-methyloxazol-4-yl-1-hydroxymethyl]-5-bromobenzofuranderivatives as follows:

    ______________________________________                                        Substituent    mp(°C.)                                                 ______________________________________                                        2-naphthyl     189-191                                                        4(CH.sub.3)C.sub.6 H.sub.4                                                                   --                                                             3(CH.sub.3)C.sub.6 H.sub.4                                                                   133-136                                                        nC.sub.6 H.sub.11                                                                            --                                                             ______________________________________                                    

PREPARATION S 2-[(2-Phenyl-5-methyloxazol-4-yl)methyl]-5-bromobenzofuran

Trifluoroacetic acid (7 ml) was added to 1.35 g of the product ofPreparation R under a nitrogen atmosphere followed by the addition of817 mg of triethylsilane and the reaction mixture stirred for 1 hour at0° C.

The reaction was diluted with 125 ml of ethyl acetate and the organicphase washed with water (1×50 ml), 1M sodium hydroxide solution (1×50ml), water (1×50 ml) and a brine solution (2×50 ml). The organic phasewas dried and concentrated in vacuo to give the crude product, which waschromatographed on silica gel (ethyl acetate-hexane; 10%-90%; v:v), 1.28g, mp 98°-100° C.

Also prepared by this method were2-[(2-substituted-5-methyloxazol-4-yl)methyl]-5-bromobenzofuranderivatives as follows:

    ______________________________________                                        Substituent    mp(°C.)                                                 ______________________________________                                        2-naphthyl     143-145                                                        4(CH.sub.3)C.sub.6 H.sub.4                                                                   --                                                             3(CH.sub.3)C.sub.6 H.sub.4                                                                   88-90                                                          nC.sub.6 H.sub.11                                                                            (oil)                                                          ______________________________________                                    

PREPARATION T 2-(2-Phenyl-5-methyloxazol-4-ylmethyl)-5-cyanobenzofuran

A mixture of 1.28 g of the product of Preparation S and 623,mg ofcuprous cyanide was treated with 10 ml of dimethylformamide and theyellow slurry heated under a nitrogen atmosphere overnight at 150° C.The mixture was cooled and poured into 15 ml of concentrated ammoniumhydroxide diluted with 5 ml of water. An additional 25 ml of ammoniumhydroxide was added and the mixture extracted with 200 ml of ethylacetate. The organic phase was separated, washed with water (3×75 ml)and a brine solution (2×50 ml) and dried over sodium sulfate. Theresidue resulting from removal of the solvent in vacuo waschromatographed on 100 g of silica gel (ethyl acetate-hexane; 20%-80%;v:v) to give 626 mg of product, mp 139°-140° C.

Also prepared by this method were2-(2-substituted-5-methyloxazol-4-ylmethyl-5-cyanobenzofuran derivativesas follows:

    ______________________________________                                        Substituent    mp(°C.)                                                 ______________________________________                                        2-naphthyl     175-176                                                        4(CH.sub.3)C.sub.6 H.sub.4                                                                   --                                                             3(CH.sub.3)C.sub.6 H.sub.4                                                                   125-126                                                        nC.sub.6 H.sub.11                                                                            85-87                                                          ______________________________________                                    

PREPARATION U5-Formyl-2-[(2-phenyl-5-methyl-4-oxazolyl)-methyl]benzofuran

A mixture of 620 mg of the product of Preparation T and 620 mg of a 50%aluminum-nickel alloy in 20 ml of, 70% formic acid was heated to refluxfor 2 hours. The reaction was cooled and the solids filtered. Thefiltrate was extracted with 200 ml of ethyl acetate and the extractwashed with water (2×75 ml), 1N sodium hydroxide solution, water (2×75ml) and a brine solution (1×50 ml). The extract was dried over sodiumsulfate and concentrated to give 544 mg of the desired product, m.p.116°-118° C.

Also prepared by this method were5-formyl-2-[(2-substituted-5-methyl-4-oxazolylmethyl]benzofuranderivatives as follows:

    ______________________________________                                        Substituent    mp(°C.)                                                 ______________________________________                                        2-naphthyl     153-155                                                        4(CH.sub.3)C.sub.6 H.sub.4                                                                   128-129                                                        3(CH.sub.3)C.sub.6 H.sub.4                                                                   --                                                             nC.sub.6 H.sub.11                                                                            (oil)                                                          ______________________________________                                    

PREPARATION V2-[(5-Methyl-2-(4-methylphenyl)-4-oxazolyl)-methyl]-5-(hydroxymethyl)benzofuran

A suspension of the product of Preparation P (8.74 g, 26.4 mmol) inethanol (260 mL) was heated until all of the solid was dissolved. Thesolution was cooled until just before a precipitate formed and NaBH₄(874 mg, 23 mmol) was added in four equal portions. The reaction wasstirred at room temperature for 1 hour and then concentrated. Theresultant solid was washed with water and the residue collected byvacuum filtration to give the title compound (7.99 g, 90%) as a tansolid: mp 156°-160° C.

Also prepared by this method were2-[(5-methyl-2-substituted-4-oxazolyl)methyl-5-(hydroxymethyl)benzofuranderivatives as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-furyl         81       123-125                                              phenyl          60       145-147                                              ______________________________________                                    

Analogous compounds having a 3-methylphenyl or n-hexyl substituent inplace of the 4-methylphenyl substituent are prepared in like manner.

Also prepared by this method were4-[2-(5-methyl-2-(2-substituted-5-methyl-4-oxazolyl)ethoxy]benzylalcohols as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-naphthyl      99       (solid)                                              2-benzofuryl    86       122-123                                              ______________________________________                                    

PREPARATION W 5-Chloromethyl-2-[(5-methyl-2-(4-methyl-

phenyl)-4-oxazolyl)methyl]benzofuran

To a suspension of the product of Preparation V (7.7 g, 23 mmol) in dryDMF (115 mL) at 0° C. was added triphenylphosphine (7.3 g, 28 mmol) andCCl₄ (4.8 mL, 51 mmol). The reaction was allowed to stir overnight atroom temperature and then poured into ice water (500 mL). This wasextracted with ethyl acetate (3×300 mL) and the combined organic layerswashed with water (2×300 mL) and brine (200 mL), dried (Na₂ SO₄)filtered and concentrated to give the crude product. Chromatographicpurification silica gel with 2:1 hexanes/ether as eluent afforded thetitle compound (6.53 g, 80%) as a yellow solid: mp 145°-146° C.

Also prepared by this method were5-chloromethyl-2-[(5-methyl-2-substituted-4-oxazolyl)methyl]benzofuranderivatives as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-furyl         100      110-113                                              phenyl           63      109-111                                              ______________________________________                                    

and 4-[2-(5-methyl-2-substituted-4-oxazolyl)ethoxy]benzyl chloridederivatives as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-naphthyl      50       124-125                                              2-benzofuryl    57       119-121                                              ______________________________________                                    

PREPARATION X 1-Benzyloxy-1-[2-[(5-methyl-2-(4-methylphenyl)-4-oxazolyl)methyl]-5-benzofuranyl]urea

Sodium hydride (1.40 g, 60% in oil, 35.1 mmol) was washed with hexanes(3×20 mL) and then diluted with dry DMF (30 mL). A solution ofO-benzylhydroxyurea (15.4 g, 92.8 mmol) and DMF (52 mL) was added andthen heated to 100° C. for 15 minutes and then cooled to roomtemperature. A solution of the product of Preparation W (6.53 g, 18.6mmol) and DMF (50 mL) was added and the reaction heated to 110° C. for 6hours. After cooling 0° C. the reaction was quenched into 500 mL waterand extracted with ethyl acetate (3×300 mL). The combined organic layerswere washed with water (3×150 mL), brine (200 mL), dried (Na₂ SO₄),filtered and concentrated to give a yellow solid. Chromatography onflorisil with gradient eluent of 1/8 ethyl acetate:hexanes to ethylacetate afforded the title compound (5.08 g, 57%) as a yellow solid: mp77°-80° C.

Also prepared by this method were1-benzyloxy-1-[2-[(5-methyl-2-substituted-4-oxazolyl)methyl]-5-benzofuranyl]ureaderivatives as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-furyl         43       129-132                                              phenyl          43       124-128                                              ______________________________________                                    

and 1-benzyloxy-1-[4-(2-(5-methyl-2-substituted-4-oxazolyl) ethoxy)benzyl]urea derivatives as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-naphthyl      48       (foam)                                               2-benzofuryl    70       105-107                                              ______________________________________                                    

PREPARATION Y5-[(N-Hydroxy-N-carbamoyl)aminomethyl]-2-[(5-methyl-2-(4-methylphenyl)oxazolyl)methyl]benzofuran

A suspension of the product of Preparation X (4.83 g, 10.0 mmol) inethanol (165 mL) was heated until homogeneous and ammonium formate (5.23g, 82.9 mmol) and 10% Pd/C (1.19 g) was added. After 2 hours at roomtemperature, the reaction was heated to 50° C. and filtered through apad of celite, the celite was then washed with several portions of hotethanol and the combined organic layers concentrated to a yellow solid.This solid was then suspended in 250 mL water and the title compound(2.87 g, 73%) was then recovered by vacuum filtration as a yellow solid:mp 183°-185° C.

Also prepared by this method were 5-[(N-hydroxy-N-carbamoyl)aminomethyl]-2-[(5-methyl-2-substituted-4-oxazolyl)methyl]benzofuranderivatives as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-furyl         75       176-179                                              phenyl          41       178-180                                              ______________________________________                                    

and 1-hydroxy-1-[4-(2-(5-methyl-2-substituted-4-oxazolyl)ethoxy)benzyl]urea derivatives as follows:

    ______________________________________                                        Substituent     Yield(%) mp(°C.)                                       ______________________________________                                        2-naphthyl      100      165-170                                              2-benzofuryl     48      177-178                                              ______________________________________                                    

We claim:
 1. A compound of the formula ##STR7## wherein R is hydrogen orC1 to C3 alkyl;R¹ and R² are taken separately, wherein R¹ is hydrogen orR⁴ and R² is --COR⁵ or --COOR⁵ ; R³, R⁴ and R⁵ are each independently C1to C9 alkyl, C3 to C7 cycloalkyl, phenyl, naphthyl, furyl, benzofuryl orthienyl or one of said groups mono- or disubstituted with C1 to C3alkyl, C1 to C3 alkoxy, C1 to C3 alkoxycarbonyl, trifluoromethyl, fluoroor chloro; and n is 0 or 1; ora pharmaceutically acceptable cationicsalt thereof.
 2. A compound according to claim 1 whereinR is methyl. 3.A compound according to claim 2 wherein R¹ is hydrogen.
 4. A compound ofthe formula ##STR8## wherein R is hydrogen or C1 to C3 alkyl;R⁶ ishydrogen or R³ ; R⁷ is hydrogen or a conventional hydroxy protectinggroup; each R³ is independently C1 to C8 alkyl, C3 to C7 cycloalkyl,phenyl, naphthyl, furyl or thienyl, or one of said groups mono- ordisubstituted with C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3alkoxycarbonyl, trifluoromethyl, fluoro or chloro; and n is 0or
 1. 5. Acompound according to claim 4 whereinR⁶ is hydrogen; and R⁷ is hydrogenor benzyl.